Effects of Alprazolam on Cortical Activity and Tremors in Patients with Essential Tremor
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Effects of Alprazolam on Cortical Activity and Tremors in
Patients with Essential Tremor
Jaime Ibáñez1*, Jesús González de la Aleja2,3, Juan A. Gallego1, Juan P. Romero2,5, Rosana A. Saı́z-
Dı́az2,3, Julián Benito-León2,3,4, Eduardo Rocon1
1 Bioengineering Group, Consejo Superior de Investigaciones Cientı́ficas, Arganda del Rey, Spain, 2 Department of Neurology, University Hospital ‘‘12 de Octubre’’,
Madrid, Spain, 3 Department of Medicine, Faculty of Medicine, Complutense University, Madrid, Spain, 4 Centro de Investigación Biomédica en Red sobre Enfermedades
Neurodegenerativas, Madrid, Spain, 5 Universidad Francisco de Vitoria, Pozuelo de Alarcón, Spain
Abstract
Background: Essential tremor (ET) is characterised by postural and action tremors with a frequency of 4–12 Hz. Previous
studies suggest that the tremor activity originates in the cerebello-thalamocortical pathways. Alprazolam is a short-acting
benzodiazepine that attenuates tremors in ET. The mechanisms that mediate the therapeutic action of alprazolam are
unknown; however, in healthy subjects, benzodiazepines increase cortical beta activity. In this study, we investigated the
effect of alprazolam both on beta and tremor-related cortical activity and on alterations in tremor presentation in ET
patients. Therefore, we characterised the dynamics of tremor and cortical activity in ET patients after alprazolam intake.
Methods: We recorded hand tremors and contralateral cortical activity in four recordings before and after a single dose of
alprazolam. We then computed the changes in tremors, cortico-muscular coherence, and cortical activity at the tremor
frequency and in the beta band.
Results: Alprazolam significantly attenuated tremors (EMG: 76.2622.68%), decreased cortical activity in the tremor
frequency range and increased cortical beta activity in all patients (P,0.05). At the same time, the cortico-muscular
coherence at the tremor frequency became non-significant (P,0.05). We also found a significant correlation (r = 0.757, P,
0.001) between the reduction in tremor severity and the increased ratio of cortical activity in the beta band to the activity
observed in the tremor frequency range.
Conclusions: This study provides the first quantitative analysis of tremor reduction following alprazolam intake. We
observed that the tremor severity decreased in association with an increased ratio of beta to tremor-related cortical activity.
We hypothesise that the increase in cortical beta activity may act as a blocking mechanism and may dampen the
pathological oscillatory activity, which in turn attenuates the observed tremor.
Citation: Ibáñez J, González de la Aleja J, Gallego JA, Romero JP, Saı́z-Dı́az RA, et al. (2014) Effects of Alprazolam on Cortical Activity and Tremors in Patients with
Essential Tremor. PLoS ONE 9(3): e93159. doi:10.1371/journal.pone.0093159
Editor: Mohammed Shamji, Toronto Western Hospital, Canada
Received December 3, 2013; Accepted March 1, 2014; Published March 25, 2014
Copyright: ß 2014 Ibáñez et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work has been partially funded by CSIC, through the program for the incorporation of tenure researches CSIC-201050I040, ‘‘Development and
clinical validation of a neuroprosthesis for tremor suppression’’, and by the EU Commission through the grant EU-FP7-2011-287739, ‘‘NeuroTREMOR’’. The funders
had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: jaime.ibanez@csic.es
Introduction interfering with the widespread pathological oscillations that occur
throughout the motor system [11]. Alprazolam, which is one of
Essential tremor (ET) is a movement disorder caused by a several pharmacological alternatives for the treatment of ET, is a
central oscillatory network and is characterised by postural and short-acting benzodiazepine with an accepted classification of
action tremors ranging in frequency from 4–12 Hz [1]. The exact probably efficacious (level B) agent [12–14].
mechanisms of tremor generation in essential tremor (ET) are still Previous studies with healthy subjects have reported increased
unknown [2,3]. However, a number of studies implicate a cortical beta rhythm activity after the intake of other benzodiaz-
neuronal loop involving cerebello-thalamocortical pathways as epines [15–18]. It is known that benzodiazepines increase the
the locus of tremorogenesis [4–9]. In particular, the analysis of affinity of the c-aminobutyric acid (GABA)-A receptor for its
coherence between cortical and muscle activity has demonstrated neurotransmitter, which increases the size of the inhibitory
the presence of tremor-related activity in cortical structures [6] postsynaptic potentials that are generated by GABA neurotrans-
and has provided a method for studying the change in cortico- mission [19]. However, it is unclear how enhancing inhibition may
muscular interaction over time [7]. increase the power of the beta and gamma rhythms [18,20].
Pharmacological treatments for ET remain limited and are only Because voluntary motor commands are projected to the
partly effective [1,10]. The action mechanisms of these drugs are targeted motor unit populations in the beta band [21–23], we
unspecified, although it is assumed that they attenuate tremors by hypothesised that the increase in cortical beta activity due to
PLOS ONE | www.plosone.org 1 March 2014 | Volume 9 | Issue 3 | e93159Effects of Alprazolam on Essential Tremor
benzodiazepines would alter the transmission of descending motor
commands. Furthermore, we expected that such an increase in
oscillatory beta activity would impede the appearance of
Male
pathological tremor-related cortical activity. Therefore, we ana-
8.2
09
58
22
N
N
N
R
4
lysed the interplay between cortical activity in the beta band and
tremor frequency after alprazolam intake to discern how this
interaction was associated with the drug effects on tremor and
Male
cortico-muscular coupling at the tremor frequency.
6.2
08
69
16
N
N
N
3
L
Methods
Patients
Male
Eight patients (two females, age 64.1613.2 years; mean 6 SD)
7.0
07
77
14
N
N
Y
2
L
were included from a general neurology outpatient clinic (the
details are provided in Table 1). All patients were diagnosed with
ET according to the Movement Disorders Society Diagnostic
Male
Criteria [24]. We excluded patients with severe tremors of the
6.2
06
65
10
15
hands or the head to avoid interference with the recordings. None
N
Y
Y
L
of the patients had other neurological conditions apart from ET or
suffered from psychiatric disorders. Additionally, none of the
patients were taking medication to treat their tremors or any other
Male
drugs that could alter their tremors. The experimental protocol
05
45
18
N
Y
R
Y
4
–
was approved by the Ethical Committee of the University Hospital
‘‘12 de Octubre’’ (Madrid) and was in accordance with the
Declaration of Helsinki. All participants provided written informed
consent.
Female
6.2
04
63
38
Recordings
Y
Y
Y
7
L
Wrist tremors on the most affected side were measured with
solid-state gyroscopes and surface EMG. Two gyroscopes
(Technaid S.L., Madrid, Spain), placed on the hand dorsum and
Male
the distal third of the forearm, measured wrist tremors by
7.0
03
44
15
17
N
N
Y
R
computing the difference between them [25,26]. The data were
sampled at 50 Hz.
Surface EMG was recorded using a grid of 1365 electrodes (1
missing electrode), with 8 mm inter-electrode distance (LISiN–OT
Female
Bioelettronica, Torino, Italy). The electrode grid was placed on the
5.2
02
wrist extensors and centred on the muscle exhibiting the clearest
80
32
32
N
Y
R
Y
tremorogenic activity; the common reference was set to the wrist
using a humidified bracelet. The data were amplified (EMGUSB,
OT Bioelettronica, Torino, Italy), band-pass filtered (10–750 Hz),
Male
and sampled at 2,048 Hz.
6.2
01
76
45
Table 1. Main baseline demographic and clinical variables.
N
N
Y
5
L
EEG signals were recorded from 16 positions (F2, F4, FCz,
FC2, FC4, FC6, Cz, C2, C4, C6, T8, CP2, CP4, CP6, Pz and P4,
according to the International 10–20 system, when the left arm
was recorded; the symmetric positions were employed when the
right arm was recorded) using passive Au electrodes. We recorded
the cortical activity from the contralateral hemisphere because the
Fahn, Tolosa, Marin Essential Tremor Rating Scale (ETRS).
cortico-muscular coherence at the tremor frequency [6,7,27,28]
and within the beta band [23,29] are best observed at this location.
The reference was set to the common voltage of the two earlobes.
AFz was used as ground. The signal was amplified (gUSBamp,
g.Tecgmbh, Graz, Austria), band-pass (0.5–60 Hz) and notch
doi:10.1371/journal.pone.0093159.t001
filtered (50 Hz), and sampled at 256 Hz.
The recording systems were synchronised with a common
digital signal. The data were analysed offline using Matlab (The
Dominant side of tremor
Mathworks Inc., Natick MA, USA) and SPSS (IBM, Chicago,
EMG tremor freq. (Hz)
Disease duration (y)
Illinois).
ET family history
Procedure
Head tremor
Age (years)
Leg tremor
The study was performed in a sound and light-attenuated room.
Gender
Patient
Patients sat in a comfortable chair with their arms supported.
ETRS
During the measurement phase, all patients were instructed to
remain relaxed with their eyes open and their gaze fixated on a
PLOS ONE | www.plosone.org 2 March 2014 | Volume 9 | Issue 3 | e93159Effects of Alprazolam on Essential Tremor
point on the wall. Patients were instructed not to eat or drink Statistical Analysis
anything (water was allowed) for 2 h before the recordings. To We used the Wilcoxon rank sum test to compare the tremor
evaluate the effects of alprazolam, patients underwent four, 4–min severity measured by the gyroscopes before (Run0) and 80 min
recording sessions at different time points relative to alprazolam after the administration of alprazolam (Run3).
administration as follows: before the administration of alprazolam The Kruskal–Wallis test was used to compare the tremor-
(Run0), immediately after (Run1), 40 min after (Run2), and related neural drive to the muscle in Run3, Run2 and Run1 with
80 min after (Run3). Postural tremors were elicited by asking respect to Run0. Significant differences between pairs of data were
patients to hold the measured hand outstretched with the palm assessed with the Games-Howell test, assuming non-equal
down and parallel to the ground. In patients who exhibited a very variances. The same test was used to compare the changes in
mild tremor before the experiment (patients 02 and 04), weight the power of cortical activity in the beta band and in the tremor-
loads of 0.5 Kg were attached to the hand to enhance the tremor frequency range and to compare the change in the ratio between
[6,7]. the activities in these two bands. In all cases, changes in Run3,
A single dose of 0.50 mg of alprazolam was administered to Run2 and Run1 were obtained with respect to Run0.
patients who weighed less than 75 kg; the remaining five patients Finally, we calculated the Spearman’s rank correlation to
received a single dose of 0.75 mg. No patient reported adverse investigate the relationship between the decrease in tremor severity
effects. Two patients were excluded due to technical problems with (in terms of neural drive to the muscle, i.e., EMG) and the change
EEG acquisition (patient 03) and to the absence of tremors during in the ratio between the EEG activity in the beta band and in the
the measurement session (patient 05). tremor frequency range, using the data from Run3, Run2 and
Run1 with respect to Run0.
Data Processing and Analysis Results are reported as the mean 6 SD, and considered
The EEG signals were spatially filtered using the Hjorth significant if P,0.05.
transform [30]. The resultant channels (FC2, FC4, C2, C4, C6,
CP2 and CP4) were used in the subsequent analyses. Artefacts Results
were removed based on visual inspection.
The tremor amplitude as measured with gyroscopes showed a
After the examination of the amplitude spectra of the gyroscope
significant (P = 0.029) reduction 80 min after the administration of
and EMG data, we defined the tremor frequency range for our
alprazolam (mean: 74.3630.2%). The mean tremor amplitudes
group of patients as 4–9 Hz (see Fig. 1). This range was used to
during Run0 and Run3 were 0.3160.34 rad2s22 and
estimate both the tremor power (measured with gyroscopes and
0.04360.049 rad2s22, respectively.
EMG) and the power of the tremor-related cortical activity.
Fig. 1 illustrates the change in tremorogenic muscle activity
To select the surface EMG channel that best characterised the across the different runs. There was a significant difference in the
tremor, we used the criterion of maximising the signal-to-noise tremor power reductions observed in Run3, Run2 and Run1
ratio (SNR) of the tremor component of the EMG signal. The compared to Run0 (P = 0.002). Post hoc analysis showed that the
SNR was defined as the ratio of the integral of the power spectral decreases in tremor power observed in Run3 (mean: 75.0617.6%)
density (PSD) within the tremor frequency range to the integral of and in Run2 (mean: 69.3617.9%) were not significantly different
the PSD of the rest of the signal, similar to [6]. This channel was from each other (P = 0.82); however, both were significantly larger
used throughout the whole analysis. than that observed in Run1 (mean: 4.6623.6%) with respect to
The percentage of tremor reduction between the first and last Run0 (P,0.001 and P,0.001, respectively).
runs (Run0 and Run3) was computed by analysing the gyroscope There were no significant differences (P = 0.917, Wilcoxon rank
data. Tremor severity was defined as the integral of the PSD of the sum test) between the tremor frequency measured with the
signal in the tremor frequency range. Before the data were band- gyroscopes (6.2260.53 Hz) and EMG (6.2060.56 Hz). The
pass filtered (2–15 Hz) to extract the tremor [26]. We also tremor frequency did not change during the recordings, although
calculated how the neural drive to the muscles related to tremors no statistics were obtained because the tremor was not clearly
was reduced after alprazolam intake by computing the percentage identifiable in some patients after alprazolam intake (see Fig. 1C).
of the tremor power decrease in Run1, Run2 and Run3 with Fig. 2 depicts the coherence between the EEG channel with the
respect to Run0 for the EMG data. largest coherence at the tremor frequency and the selected EMG
Cortico-muscular coherence was computed to assess how the channel. The coherence at the tremor frequency in Run0 was
tremor-related cortical drive to the muscle varied due to the effect significant (P,0.05) for all patients. In Run3, the coherence at the
of alprazolam. We calculated the coherence between all the tremor frequency decreased in all cases and fell below the
processed EEG channels and the rectified EMG at the electrode significance threshold in five out of seven patients. In the case of
previously selected [31], and we chose the EEG channel that patient 07, the significant coherence in Run3 was accompanied by
exhibited the largest peak at the tremor frequency for the the observed rebound of EMG tremor power in Run3 with respect
subsequent calculations. We used the method for coherence to Run2 (Fig. 1).
estimation proposed in [32]: the signals were divided into epochs Fig. 3 shows the time course of the EEG power spectrum along
of 1 s, and their individual spectra and cross-spectra were the runs. Relative to Run0, there was a significant increase in the
computed. Coherence was estimated as the ratio between the ratio between the beta and tremor-related cortical activities for
squared cross-spectrum and the product of the two individual Run3, Run2 and Run1 (P = 0.003). Post hoc analysis showed no
power spectra [6,32]. The confidence limit was obtained as in significant difference between Run3 (mean 129.2696.7%) and
[33]. Run2 (mean 94.0648.5%) (P = 0.68), but both were significantly
To study how alprazolam affected the tremor-related cortical larger than Run1 (mean 9.81617.6%) (P = 0.039 and P = 0.007,
activity and the cortical activity in the beta band, we assessed the respectively).
changes in the EEG spectra by calculating the integral of the PSD When considered separately, the observed pattern of changes in
at the selected channel in the tremor frequency range (4–9 Hz, see cortical beta activity and in cortical activity within the tremor
above) and in the beta band (13–30 Hz). frequency range were similar. The increases in beta power in
PLOS ONE | www.plosone.org 3 March 2014 | Volume 9 | Issue 3 | e93159Effects of Alprazolam on Essential Tremor
Figure 1. Time course of the tremor power measured with EMG. (A) Time course of the raw EMG (the amplitude scale is the same for all
subjects); (B) PSD of the EMG signals (one panel per patient).
doi:10.1371/journal.pone.0093159.g001
Run1, Run2 and Run3 with respect to Run0 (5.763.6%, Discussion
54.4626.8% and 64.8629.2% respectively) were significantly
different (P = 0.002). Post hoc analyses showed that statistical This study characterises the dynamics of tremor and cortical
significance was achieved for the comparison between Run1 and activity in ET patients after alprazolam intake. We observed
Run2 (P = 0.007) and between Run1 and Run3 (P = 0.004), significant changes in the measured tremor as well as in the
whereas the difference between Run2 and Run3 was not cortical activity both in the beta band and in the tremor frequency
statistically significant (P = 0.77). The decrease of cortical activity range due to the effects of the drug. These changes revealed a
in the tremor frequency range was also significantly different in significant correlation between tremor reduction and the relative
Run1 (1.7615.4%), Run2 (18.1616.2%) and Run3 (23.1616.1%) change in cortical activity in the beta and tremor-related bands.
with respect to Run0 (P = 0.035). However, post hoc analyses of The study also provides the first quantitative evidence of tremor
pairwise group comparisons did not achieve statistical significance. changes after a single dose of alprazolam. Two previous studies
A graph of these results is depicted in Fig. 4, where it is shown that, showed a significant improvement in tremor rating scales after
after alprazolam intake, the cortical activity within the tremor treating ET patients with alprazolam. Specifically, these studies
frequency range decreases and the cortical beta activity increases. reported a 30% reduction in a double-blind placebo-controlled
This effect can be observed for all patients 80 min after trial [14], a 25% decrease in tremor intensity rated by functional
alprazolam intake. scores and a 46% increase in the global improvement scale by
There was a significant correlation (r = 0.757, P,0.001) patient self-evaluation [13]. Here, we confirm these results
between the tremor power decrease (as measured with EMG) quantitatively by showing a significant tremor reduction of
and the increased ratio of beta to tremor-related activity in cortical 69.4% and 75.8% according to the EMG data (i.e., the neural
areas contralateral to the measured hand (in the EEG channel input to the muscle related to tremor) acquired 40 and 80 min
where significant cortico-muscular coupling was best observed, after a single dose of alprazolam. The timing of the observed
Fig. 4). This relation also held when analysing separately the effects is also consistent with the time of peak concentration of
results of each patient, i.e., all of the patients presented a positive alprazolam reported for healthy elderly subjects (48618 min) [34].
relationship between both variables, as shown in Fig. 5. The use of a low, single dose of alprazolam was aimed to avoid
drowsiness that induced EEG changes consistent with sedation
and were not related to the hypothesised anti-tremorogenic effect.
PLOS ONE | www.plosone.org 4 March 2014 | Volume 9 | Issue 3 | e93159Effects of Alprazolam on Essential Tremor
Figure 3. PSDs of the EEG data in the optimal channel for each
patient. The shaded areas represent the tremor frequency range
(yellow) and the beta band (green), as used to evaluate changes in the
cortical activity. Each panel represents a different patient.
Figure 2. Cortico-muscular coherence. Obtained from Run0 and
doi:10.1371/journal.pone.0093159.g003
Run3 (Run2 is included for patient 07 only). Each panel represents a
different patient. The significance level (P,0.05) is also displayed (solid
grey line). We observed a significant increase in cortical beta activity in all
doi:10.1371/journal.pone.0093159.g002 ET patients during a period after alprazolam intake, consistent
with previous research addressing the effects of other benzodiaz-
In fact, the observed increase of EEG activity in the beta band epines in healthy subjects [16,17]. Interestingly, the power of the
argues against a sedative effect of alprazolam because beta activity EEG activity at the beta band is also enhanced in alcoholics [39]
is considered an index of cortical arousal [35]. or after a small single dose of alcohol [40], and in 50–90% of ET
We assessed the change in strength of cortico-muscular coupling patients, alcohol acts to reduce the tremor amplitude [12,41].
due to the effect of alprazolam. As expected [6,7,27,36], the While the precise mode of action of ethanol in ET has not been
coherence values at the tremor frequency were significant in all established [42], its principal effect is likely mediated by the
patients before drug intake. The coherence decreased 80 min after potentiation of GABA-A receptors [43]. Although the effect of
alprazolam intake and was below the significance threshold in all these substances increasing the beta power measured with EEG
could not be related to its anti-tremorogenic effects, we observed a
patients, except for patients 07 and 08. Interestingly, patient
significant relationship between an increase in the ratio of beta to
07 also presented a rebound of tremor severity in Run3 compared
tremor-related cortical activity and a reduction in contralateral
to Run2 (according to the EMG data) and demonstrated the
postural tremor. Indeed, we observed this dependency for each
highest levels of the cortical beta activity 40 min after drug
patient individually (Fig. 4). We acknowledge that this finding may
administration. These data suggest an earlier onset and termina-
be an epiphenomenon or a consequence, albeit not necessarily
tion of the effects of alprazolam in this patient. Additionally, we
direct, of the biochemical effect of alprazolam on the brain.
observed a decrease in the power of cortical activity in the tremor
Nevertheless, considering that during sustained motor contraction
frequency range in the EEG channel showing the largest
the activity within cortical motor areas and their target muscles is
coherence at the tremor frequency. Taken together, these results
synchronised in the beta-range [22,23,44–46], we hypothesise that
suggest that the pathological oscillatory activity in the cortex
the increased physiological beta activity in the primary motor
decreased when the drug started to take effect. On the other hand,
cortex may be interfering, at least in part, with the coupling of
coherent activity in the beta band was not evident in our results
pathological oscillatory networks involved in the generation of
either from the beginning of the session or during subsequent runs.
tremor in ET.
This finding is in contrast with the robust coherence at the beta
Since EEG technology has limited spatial resolution, it cannot
band observed in other studies; however, here, the patients
be stated from our data that the cortical changes observed at the
performed mild contractions to hold their hands extended, which tremor frequency after alprazolam intake are exclusively due to
explains the lack of meaningful results in this regard [37,38]. changes in the tor cortex. Indeed, previous studies on cortico-
PLOS ONE | www.plosone.org 5 March 2014 | Volume 9 | Issue 3 | e93159Effects of Alprazolam on Essential Tremor
Figure 5. Relationship between changes in tremor power and
the ratio between the beta and the tremor-related cortical
activities for all patients and runs. Run1, Run2 and Run3 (all with
N
respect to Run0) are represented with the symbols , # and X,
respectively.
doi:10.1371/journal.pone.0093159.g005
patients undergoing stereotaxy were effective at reducing tremor
[54].
Results presented here could be of pathophysiological interest,
Figure 4. Changes (in %) of the cortical beta and tremor related providing biomarkers for alprazolam induced cortical activity
activities in Run1, Run2, and Run3 with respect to Run0. (A) modulation in vivo. We also consider that the interplay between
Decrease in the power of cortical activity within the tremor frequency cortical activity in the beta band and pathological tremor-related
range. (B) Increase in the power of the beta band. (C) Increase in the cortical activity could be an easily measurable marker of efficiency,
ratio between the power in the beta band and in the tremor frequency providing new tools to assess the effect of novel therapeutic
range.
doi:10.1371/journal.pone.0093159.g004
strategies that enhance GABAergic inhibition with other mecha-
nisms instead of benzodiazepines.
Finally, the authors acknowledge several limitations of the
muscular coherence in ET have pointed to a combined effect of
present study but consider that their impact on the conclusions is
the afferent and efferent tracts [7]. It has also been shown that
minor. First, we recruited a small group of patients and thus our
existing techniques to detect the actual direction of information
results might not be generalisable to a broader population of ET
flow are not always precise enough [47]. The main purpose of the
cases. However, the homogeneity of the results obtained from all
present study is to characterize the interaction between the central
the patients separately (Fig. 5 shows that the identified positive
(cortical) rhythms and the peripheral tremor. Indeed, we also
tendency is present in all cases) reinforces the hypothesis proposed
observed a significant correlation between the tremor reduction
in this study. Second, we did not use a placebo group. However,
and the increase in cortical beta activity by the effects of
our data do not indicate that any of the patients experienced
alprazolam alone (results no included here). In that case, the
placebo effects given that the observed reduction in tremor severity
significance of the correlation was slightly smaller than the one
4 min after alprazolam intake was negligible compared to
obtained using the ratio between the beta and the tremor-related
subsequent runs (Fig. 1). We consider that the results were not
cortical activities but also suggested that there are changes in
influenced by expectancy bias because the patients had never
cortical beta activity when tremor is reduced.
received alprazolam as treatment before and were unfamiliar with
There is increasing evidence suggesting that Purkinje cells (PC)
the therapeutic effects of the drug to alleviate tremors.
and connected neuronal populations are centrally involved in the
In conclusion, we have shown that alprazolam attenuates
generation of tremor in ET [42,48–51]. Regardless of whether ET
tremors in ET and increases the ratio between the beta and
is a neurodegenerative disease affecting PC [51], or the result of
tremor-related cortical activity as well as decreases the strength of
pacemaking neurons in the inferior olive [48–50], these structures
cortico-muscular coupling at the tremor frequency. We hypothe-
are controlled by GABAergic connections [52]. Recently, Paris-
sise that the increase in cortical beta activity due to the effects of
Robidas et al. reported a post-mortem decrease in GABA
alprazolam acts as a blocking mechanism of activity in patholog-
receptors in the dentate nucleus of the cerebellum from individuals
ical neural networks, which leads to a reduction of tremors in ET
with ET (compared with controls or individuals with Parkinson’s
patients. This is the first study to describe the neurophysiological
disease) that could result in disinhibition of cerebellar pacemaker
changes occurring in ET patients after benzodiazepine adminis-
output activity [53]. Therefore, we are aware that the GABAergic
tration, and it is expected that future experiments will identify
effect of alprazolam would not be restricted to the sensorimotor
other drugs that reduce tremors in ET and that will enhance our
cortex but could be spread through cerebello-thalamic pathways.
understanding of the pathophysiology of this disease and its
Indeed, localised microinjections of the GABA-A agonist musci-
response to different treatments.
mol into the ventral intermediate nucleus (in areas with
electrophysiologically identified tremor-synchronous cells) of ET
PLOS ONE | www.plosone.org 6 March 2014 | Volume 9 | Issue 3 | e93159Effects of Alprazolam on Essential Tremor
Author Contributions the data: JI JGdlA JAG. Contributed reagents/materials/analysis tools: JI
JGdlA JAG. Wrote the paper: JI JGdlA JAG JPR JBL ER. Patient
Conceived and designed the experiments: JI JGdlA JAG JPR RASD JBL recruitment: JPR RASD JGdlA. Looked for funding: ER.
ER. Performed the experiments: JI JGdlA JAG JPR RASD ER. Analyzed
References
1. Benito-León J, Louis ED (2006) Essential tremor: emerging views of a common 27. Hellwig B, Schelter B, Guschlbauer B, Timmer J, Lücking C (2003) Dynamic
disorder. Nat. Clin. Pract. Neurol. 2(12): 666–78; synchronisation of central oscillators in essential tremor. Clin. Neurophysiol.
2. Elble RJ, Deuschl G (2009) An update on essential tremor. Curr. Neurol. 114(8): 1462–7.
Neurosci. Rep. 9(4): 273–7. 28. Timmermann L, Gross J, Dirks M, Volkmann J, Freund HJ, et al. (2002) The
3. Louis ED, Babij R, Cortés E, Vonsattel J-PG, Faust PL (2013) The inferior cerebral oscillatory network of parkinsonian resting tremor. Brain. 126(1): 199–
olivary nucleus: A postmortem study of essential tremor cases versus controls. 212.
Mov. Disord. 28(6): 779–86. 29. Negro F, Farina D (2011) Linear transmission of cortical oscillations to the
4. Benito-León J, Alvarez-Linera J, Hernández-Tamames JA, Alonso-Navarro H, neural drive to muscles is mediated by common projections to populations of
Jiménez-Jiménez FJ, et al. (2009) Brain structural changes in essential tremor: motoneurons in humans. J. Physiol. 589(Pt 3): 629–37.
voxel-based morphometry at 3-Tesla. J. Neurol. Sci. 287(1–2): 138–42. 30. Hjorth B (1975) An On-Line Transformation of EEG Scalp Potentials into
5. Hua SE, Lenz Fa, Zirh T a, Reich SG, Dougherty PM (1998) Thalamic Orthogonal Source Derivations. Electroencephalogr. Clin. Neurophysiol. 39(5):
neuronal activity correlated with essential tremor. J. Neurol. Neurosurg. 526–30.
Psychiatry. 64(2): 273–6. 31. Farina D, Negro F, Jiang N (2013) Identification of common synaptic inputs to
6. Hellwig B, Häubler S, Schelter B, Lauk M, Guschlbauer B, et al. (2001) Tremor- motor neurons from the rectified electromyogram. J. Physiol. 591(Pt 10): 2403–
correlated cortical activity in essential tremor. Lancet. 357: 519–23. 18.
7. Raethjen J, Govindan RB, Kopper F, Muthuraman M, Deuschl G (2007) 32. Halliday DM, Rosenberg JR, Amjad aM, Breeze P, Conway Ba, et al. (1995) A
Cortical involvement in the generation of essential tremor. J. Neurophysiol. framework for the analysis of mixed time series/point process data–theory and
97(5): 3219–28. application to the study of physiological tremor, single motor unit discharges and
8. Raethjen J, Deuschl G (2012) The oscillating central network of Essential electromyograms. Prog. Biophys. Mol. Biol. 64(2–3): 237–78.
tremor. Clin Neurophysiol. International Federation of Clinical Neurophysiol- 33. Rosenberg JR, Amjad AM, Breeze P, Brillinger DR, Halliday DM (1989) The
ogy; 123(1): 61–4. Fourier approach to the identification of functional coupling between neuronal
9. Schnitzler A, Münks C, Butz M, Timmermann L, Gross J (2009) Synchronized spike trains. Prog. Biophys. Mol. Biol. 53(1): 1–31.
brain network associated with essential tremor as revealed by magnetoenceph- 34. Kaplan GB, Greenblatt DJ, Ehrenberg BL, Goddard JE, Harmatz JS, et al.
alography. Mov. Disord. 24(11): 1629–35. (1998) Single-dose pharmacokinetics and pharmacodynamics of alprazolam in
10. Benito-León J, Louis ED (2011) Update on essential tremor. Minerva Med. elderly and young subjects. J. Clin. Pharmacol. 38(1): 14–21.
102(6): 417–40. 35. Niedermeyer E (2005) The normal EEG of the waking adult. In: Niedermeyer E,
11. Deuschl G, Raethjen J, Hellriegel H, Elble R (2011) Treatment of patients with da Silva FHL, editors. Electroencephalogr: Basic Principles, Clinical Applica-
essential tremor. Lancet Neurol. 10(2): 148–61. tions and Related Fields, fifth Ed. Philadelphia: Lippincott Williams and Wilkins;
12. Zesiewicz TA, Elble RJ, Louis ED, Gronseth GS, Ondo WG, et al. (2011) p.167–92.
Evidence-based guideline update: treatment of essential tremor: report of the 36. Muthuraman M, Heute U, Arning K, Anwar AR, Elble R, et al. (2012)
Quality Standards subcommittee of the American Academy of Neurology. Oscillating central motor networks in pathological tremors and voluntary
Neurology. 77(19): 1752–5. movements. What makes the difference? Neuroimage. 60(2): 1331–9.
13. Gunal DI, Afsar N, Bekiroglu N, Aktan S (2000) New alternative agents in 37. Chakarov V, Naranjo JR, Schulte-Mönting J, Omlor W, Huethe F, et al. (2009)
essential tremor therapy: double-blind placebo-controlled study of alprazolam Beta-range EEG-EMG coherence with isometric compensation for increasing
and acetazolamide. Neurol. Sci. 21(5): 315–7. modulated low-level forces. J. Neurophysiol. 102(2): 1115–20.
14. Huber SJ, Paulson GW (1988) Efficacy of alprazolam for essential tremor. 38. Baker MR, Baker SN (2012) Beta-adrenergic modulation of tremor and
Neurology. 38(2): 241–3. corticomuscular coherence in humans. PLoS One. 7(11):e49088.
15. Lindhardt K, Gizurarson S, Stefánsson SB, Olafsson DR, Bechgaard E (2001) 39. Rangaswamy M, Porjesz B, Chorlian DB, Wang K, Jones KA, et al. (2002) Beta
Electroencephalographic effects and serum concentrations after intranasal and power in the EEG of alcoholics. Biol. Psychiatry. 52(8): 831–42.
intravenous administration of diazepam to healthy volunteers. Br. J. Clin. 40. Ilan AB, Gevins A (2001) Prolonged neurophysiological effects of cumulative
Pharmacol. 52(5): 521–7. wine drinking. Alcohol. 25(3): 137–52.
16. Baker MR, Baker SN (2002) The effect of diazepam on motor cortical 41. Growdon JH, Shahani BT, Young RR (1975) The effect of alcohol on essential
oscillations and corticomuscular coherence studied in man. J. Physiol. 546(3): tremor. Neurology. 25(3): 259–62.
931–42.
42. Boecker H, Wills a J, Ceballos-Baumann A, Samuel M, Thompson PD, et al.
17. Jensen O, Goel P, Kopell N, Pohja M, Hari R, et al. (2005) On the human
(1996) The effect of ethanol on alcohol-responsive essential tremor: a positron
sensorimotor-cortex beta rhythm: sources and modeling. Neuroimage. 26(2):
emission tomography study. Ann. Neurol. 39(5): 650–8.
347–55.
43. Wallner M, Hanchar HJ, Olsen RW (2003) Ethanol enhances alpha 4 beta 3
18. Hall SD, Barnes GR, Furlong PL, Seri S, Hillebrand A (2010) Neuronal network
delta and alpha 6 beta 3 delta gamma-aminobutyric acid type A receptors at low
pharmacodynamics of GABAergic modulation in the human cortex determined
concentrations known to affect humans. Proc. Natl. Acad. Sci. 100(25): 15218–
using pharmaco-magnetoencephalography. Hum. Brain Mapp. 31(4): 581–94.
23.
19. Connors BW, Malenka RC, Silva LR (1988) Two inhibitory postsynaptic
44. Baker SN (2007) Oscillatory interactions between sensorimotor cortex and the
potentials, and GABAA and GABAB receptor-mediated responses in neocortex
periphery. Curr. Opin. Neurobiol. 17(6): 649–55.
of rat and cat. J. Physiol. 406: 443–68.
45. Brown P (2000) Cortical drives to human muscle: the Piper and related rhythms.
20. Minc D, Machado S, Bastos VH, Machado D, Cunha M, et al. (2010) Gamma
Prog. Neurobiol. 60(1): 97–108.
band oscillations under influence of bromazepam during a sensorimotor
integration task: an EEG coherence study. Neurosci. Lett. 469(1): 145–9. 46. Halliday DM, Conway B a, Farmer SF, Rosenberg JR (1998) Using
electroencephalography to study functional coupling between cortical activity
21. Petersen TH, Willerslev-Olsen M, Conway B a, Nielsen JB (2012) The motor
cortex drives the muscles during walking in human subjects. J. Physiol. 590(Pt and electromyograms during voluntary contractions in humans. Neurosci. Lett.
10): 2443–52. 241(1): 5–8.
22. Kilner JM, Baker SN, Salenius S, Hari R, Lemon RN (2000) Human Cortical 47. Sommerlade L, Amtage F, Lapp O, Hellwig B, Lücking CH, et al. (2011) On the
Muscle Coherence Is Directly Related to Specific Motor Parameters. J. estimation of the direction of information flow in networks of dynamical systems.
Neurosci. 20(23): 8838–45. J. Neurosci. Methods. 196(1): 182–9.
23. Conway Ba, Halliday DM, Farmer SF, Shahani U, Maas P, et al. (1995) 48. Jenkins IH, Bain PG, Colebatch JG, Thompson PD, Findley LJ, et al. (1993) A
Synchronization between motor cortex and spinal motoneuronal pool during the positron emission tomography study of essential tremor: evidence for overactivity
performance of a maintained motor task in man. J. Physiol. 1995 489 (Pt 3): of cerebellar connections. Ann. Neurol. 34(1): 82–90.
917–24. 49. Wilms H, Sievers J, Deuschl G (1999) Animal models of tremor. Mov. Disord.
24. Deuschl G, Bain P, Brin M (1998) Consensus statement of the Movement 14(4): 557–71.
Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov. Disord. 13 50. Park Y-G, Park H-Y, Lee CJ, Choi S, Jo S, et al. (2010) Ca(V)3.1 is a tremor
Suppl 3: 2–23. rhythm pacemaker in the inferior olive. Proc. Natl. Acad. Sci. 107(23): 10731–6.
25. Rocon E, Andrade AO, Pons JL, Kyberd P, Nasuto SJ (2006) Empirical mode 51. Babij R, Lee M, Cortés E, Vonsattel J-PG, Faust PL, et al. (2013) Purkinje cell
decomposition: a novel technique for the study of tremor time series. Med. Biol. axonal anatomy: quantifying morphometric changes in essential tremor versus
Eng. Comput. 44(7): 569–82. control brains. Brain. 136(Pt 10): 3051–61.
26. Gallego JA, Rocon E, Roa JO, Moreno JC, Pons JL (2010) Real-time estimation 52. Bazzigaluppi P, Ruigrok T, Saisan P, De Zeeuw CI, de Jeu M (2012) Properties
of pathological tremor parameters from gyroscope data. Sensors (Basel). 10(3): of the nucleo-olivary pathway: an in vivo whole-cell patch clamp study. Zhang
2129–49. LI, editor. PLoS One. 7(9):e46360.
PLOS ONE | www.plosone.org 7 March 2014 | Volume 9 | Issue 3 | e93159Effects of Alprazolam on Essential Tremor
53. Paris-Robidas S, Brochu E, Sintes M, Emond V, Bousquet M, et al. (2012) 54. Pahapill PA, Levy R, Dostrovsky JO, Davis KD, Rezai AR, et al. (1999) Tremor
Defective dentate nucleus GABA receptors in essential tremor. Brain. 135(Pt 1): arrest with thalamic microinjections of muscimol in patients with essential
105–16. tremor. Ann. Neurol. 46(2): 249–52.
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